Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Its cause is unknown, but both genetic and environmental factors are involved. Emerging data show that genetic variants associated with RA differ by race/ethnicity. RA is uncommon in black Africans, but it is common among African-Americans, suggesting that there may be protective factors in ancestral Africans. Osteoporosis, a common co-morbid condition with RA, is much less common among African-Americans than among persons of European ancestry. Genetic factors associated with RA and its radiographic severity have been extensively studied in persons of European and of Asian ancestry, but the lack of large datasets has precluded similar analyses in African-Americans. We are uniquely positioned to analyze the genetics of RA in African- Americans through the extensive data collected from the NIH-funded CLEAR (Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis) Registry, its funded ancillary studies, and other data collections. We seek to identify genetic influences on susceptibility to, or protection from, RA in African-Americans by analyzing a total of 3,200 African-Americans. In Aim 1, we will perform a genome-wide association study (GWAS) using the Illumina Human 1M Duo BeadChip in 1,600 African-Americans (800 with anti-CCP+ RA and 800 controls). Aim 2 will replicate and extend these findings by analyzing ~12,000 single nucleotide polymorphisms (SNPs) in an independent set of 1,600 African-Americans (800 CCP+ RA patients and 800 controls). In Aim 3, we will perform additional mapping of the genetic regions associated with RA. In addition, we will perform exploratory analyses of genetic data with existing data on RA-related phenotypes, including radiographic severity at 3 years disease duration, and bone mineral density in early RA and controls. We will also use existing gene expression microarray data from peripheral blood mononuclear cells in CLEAR patients to identify expression quantitative trait loci (eQTL) (nearby or distant genetic variants that influence gene expression), particularly those associated with radiographic severity of RA. This proposal will translate advances in clinical rheumatology, biotechnology, and statistical genetics into new information to improve diagnosis, or assessment of prognosis, or develop targeted therapies for RA in African-Americans.